Tetrahydroxanthone derivatives

ABSTRACT

A tetrahydroxanthone derivative represented by the general formula: ##STR1## wherein R is a hydrogen atom, a hydroxyl, cyano, lower alkyl, lower alkoxy, lower acyloxy, benzoyloxy or tetrazolyl group, or ##STR2## (R 3  is a hydrogen atom, R 4  is a hydrogen atom, a phenyl group which may be optionally substituted, or a tetrazolyl group; or R 3  and R 4  commonly form a ring together with the adjacent nitrogen atom and another nitrogen atom or an oxygen atom); R 1  is a hydrogen or halogen atom, a lower alkyl, cyano, carboxyl or tetrazolyl group, or ##STR3## (R 5  is a hydrogen atom, R 6  is a phenyl group which may be optionally substituted, or a tetrazolyl group; or R 5  and R 6  commonly form a ring together with the adjacent nitrogen atom and an oxygen atom); and R 2  is a hydrogen or halogen atom, or a lower alkyl group; with the proviso that neither R nor R 1  is a hydrogen atom; when R is --CONH 2 , R 1  and R 2  are not respectively a hydrogen atom nor a hydrogen or halogen atom, or a lower alkyl group; and R 2  and R 1  are not respectively a hydrogen atom nor a halogen atom or a lower alkyl group. Exhibits anti-allergic, anti-inflammatory, analgesic, inhibitory and asthma-treating activities.

BACKGROUND OF THE INVENTION

The present invention relates to novel tetrahydroxanthone derivatives, and more particularly to a tetrahydroxanthone derivative represented by the following general formula (I): ##STR4## wherein R is a hydrogen atom, a hydroxyl, cyano, lower alkyl, lower alkoxy, lower acyloxy, benzoyloxy or tetrazolyl group, or ##STR5## (R₃ is a hydrogen atom, and R₄ is a hydrogen atom, a phenyl group which may be optionally substituted, or a tetrazolyl group; or R₃ and R₄ commonly form a ring together with the adjacent nitrogen atom and another nitrogen atom or an oxygen atom); R₁ is a hydrogen or halogen atom, a lower alkyl, cyano, carboxyl or tetrazolyl group, or ##STR6## (R₅ is a hydrogen atom, and R₆ is a phenyl group which may be optionally substituted, or a tetrazolyl group; or R₅ and R₆ commonly form a ring together with the adjacent nitrogen atom and an oxygen atom); and R₂ is a hydrogen or halogen atom, or a lower alkyl group; with the proviso that neither R nor R₁ is a hydrogen atom; when R is --CONH₂, R₁ and R₂ are not respectively a hydrogen atom nor a hydrogen or halogen atom, or a lower alkyl group; and R₂ and R₁ are not respectively a hydrogen atom nor a halogen atom or a lower alkyl group.

Tetrahydroxanthone derivatives having the formula (I) according to the present invention exhibit anti-allergic, anti-inflammatory, analgesic and inhibitory effects on PCA (Passive Cutaneous Anaphylaxis) and hence are extremely useful as pharmaceutical products.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The compounds of the formula (I) according to the invention can be prepared, for example, by any one of the methods described hereinafter.

Method (1)

An acylated salicylic acid of the formula (II) or its reactive derivative at the carboxylic group is reacted with a compound having the formula (III) to obtain a tetrahydroxanthone derivative (Ia). ##STR7## wherein R₂ is a hydrogen or halogen atom, or a lower alkyl group, R₇ is a lower alkyl group, R₈ is a hydrogen atom, or a lower alkyl, lower alkoxy, lower acyloxy or benzoyloxy group, and X is a halogen atom.

The reactive derivative of the formula (II) is one member selected from an acid anhydride, an acid halogenide and the like. For example, one such acylated salicylic acid of the formula (II) can be reacted with a chlorocarbonic ester in the presence of a base such as triethyl amine or the like to obtain an anhydride of its acid mixture.

The reaction can be carried out in a suitable solvent inert to the reaction, such as dichloromethane, chloroform, benzene, toluene, ether or the like, at room temperature and with stirring for a period of 3 to 5 hours. Subsequently, the solvent is removed by distillation from the reaction mixture to give a residue which is then combined with an aqueous basic solution of pyridine, pyrrolidine, piperidine or the like, or an aqueous acidic solution of hydrochloric acid or sulfuric acid or the like. The resulting mixture is heated under refluxing conditions to obtain one such compound of the formula (Ia).

Method (2)

A halogeno derivative (IV) is cyanated to obtain a cyano derivative (Ib) of tetrahydroxanthone. ##STR8## wherein R₉ is a hydrogen atom, or a hydroxyl, benzoyloxy, lower alkyl, lower alkoxy or lower acyloxy group, and R₂ and X each have the same significance as defined above.

The cyanation reaction in this method is carried out, for example, by reacting the compound of the formula (IV) with a cyanating reagent such as cuprous cyanide in a solvent such as N-methyl-2-pyrrolidone at a temperature of 160° to 200° C. for 1 to 3 hours and then by treating the reaction mixture in a mixed solution of water-ferric chloride-concentrated hydrochloric acid at a temperature of 60° to 100° C. for 30 minutes.

Method (3)

An acid amide derivative (V) of tetrahydroxanthone is dehydrated to obtain a cyano derivative (Ic) of tetrahydroxanthone. ##STR9## wherein R₁₀ is a hydrogen atom or an alkyl group, and R₂ has the same significance as defined above.

The dehydration reaction is carried out by agitating the compound of the formula (V) in a solvent, for example, dimethyl formamide or the like, under the action of thionyl chloride or the like at a temperature of about 0° C.

Method (4)

The cyano derivative (Ib) or (Ic) of tetrahydroxanthone is hydrolyzed to obtain a carboxylic acid derivative (Id) of tetrahydroxanthone. ##STR10## wherein R₁₂ is a hydrogen atom or a lower alkyl group when R₁₁ is a carboxyl group, R₁₁ is a hydrogen atom or a lower alkyl group when R₁₂ is a carboxyl group, and R₂, R₉ and R₁₀ each have the same significance as defined above.

The hydrolysis reaction of the compound of the formula (Ib) or (Ic) can be conducted by any conventional method, but it is preferable to hydrolyze the compound in such a solvent as, for example, of water-sulfuric acid-acetic acid, or water-sulfuric acid.

Method (B 5)

A carboxylic acid derivative (Id) of tetrahydroxanthone is reacted with an amine compound (VI) or (VII) to obtain a tetrahydroxanthone derivative (Ie). ##STR11## wherein R₁₄ is a hydrogen atom, or a hydroxyl, benzoyloxy, lower alkyl, lower alkoxy or lower acyloxy group when R₁₃ is ##STR12## R₁₃ is a hydrogen or halogen atom, or a lower alkyl group when R₁₄ is ##STR13## and R₂, R₃, R₄, R₅, R₆, R₁₁ and R₁₂ each have the same significance as defined above; with the proviso that when R₁₄ is --CONH₂, R₁₃ and R₂ are not respectively a hydrogen atom nor a hydrogen or halogen atom, or a lower alkyl group; and R₂ and R₁₃ are not respectively a hydrogen atom nor a halogen atom or a lower alkyl group.

The reaction in this method can be conducted by any method which is generally employed for the production of acid amides.

Method (6)

A cyano derivative (Ib) or (Ic) of tetrahydroxanthone is reacted with sodium azide to obtain a tetrazolyl derivative (If) of tetrahydroxanthone. ##STR14## wherein R₁₆ is a hydrogen atom, or a hydroxyl, benzoyloxy, lower alkyl, lower alkoxy or lower acyloxy group when R₁₅ is a tetrazolyl group, R₁₅ is a hydrogen atom or a lower alkyl group when R₁₆ is a tetrazolyl group, and R₂ has the same significance as defined above.

Method (7)

The compounds of the formula (I) in which R is a hydroxyl group can be prepared by debenzoylating their corresponding compounds of the same formula in which R is a benzoyloxy group. ##STR15## wherein R₁ and R₂ each have the same significance as defined above.

Method (8)

A hydroxyl derivative (Ih) of tetrahydroxanthone is reacted with an alkylating agent to obtain an alkoxyl derivative (Ii) of tetrahydroxanthone. ##STR16## wherein R₁₇ is a lower alkyl group, and R₁ and R₂ each have the same significance as defined above.

Method (9)

One such hydroxyl derivative (Ih) of tetrahydroxanthone is reacted with an acylating agent to obtain an acyloxyl derivative (Ik) of tetrahydroxanthone. ##STR17## wherein R₁₈ is a lower acyl group, and R₁ and R₂ each have the same significance as defined above.

Among alkylating agents and acylating agents to be utilized in method (8) and method (9), respectively, there are various reagents commonly used for their respective purposes which include, for example, dialkyl sulfates and alkyl halides as such alkylating agents, and acid halides, acid anhydrides and anhydrides of acid mixtures as such acylating agents.

The compounds of the formula (I) according to the present invention were subjected to pharmacological and acute toxic tests. The results are described below.

1. Pharmacological effects (1) Inhibitory effects on histamine release

An anti-ovalbumin (OA) mouse serum (IgE like antibody, PCA titer; 1:400-1:800) was diluted 20 times with physiological saline. A male Sprague-Dawley (SD) rat weighing 300-400 g was passively sensitized by intraperitoneal administration of 5 ml of the diluted serum. 48 Hours later, the rat was decapitated and exsanguinated. 10 ml of Tyrode's solution containing 5 units/ml of heparin was then injected into the peritoneal cavity of the rat. After mixing the solution by gentle massage for 60 seconds, the fluid in the peritoneal cavity was collected and then centrifuged for 5 minutes at 120×g to harvest peritoneal cells. The peritoneal cells were suspended in Tyrode's solution so as to adjust the concentration of 10⁶ cells/ml. After preincubating 1.6 ml of the cell suspension for 4 minutes at 37° C., 0.2 ml of each test compound solution and 0.2 ml of OA solution (100 μg/ml) were added simultaneously and thereafter incubated for 10 minutes at 37° C. The reaction was terminated by ice-cooling the mixture, and the thus incubated solution was centrifuged for 5 minutes at 670×g to divide the same into a cell pellet and a supernatant liquid phase. The histamine content in each of the phases was determined by the fluorometric method of Grant et al*. Each tested pharmaceutical compound was used by dissolving it in Tyrode's solution prior to its use.

(2) Inhibitory effects on passive cutaneous anaphylaxis (PCA)

A male SD rat weighing about 300 g was used, whose hair on the back had been shaved with an electric clipper. The back skin was passively sensitized by intradermal injection of 0.1 ml of anti-OA mouse serum (IgE like antibody) which had been diluted to three concentration levels. 4 Hours later, the rat was challenged by intravenous injection of an antigen solution of 2 ml/kg containing OA (1 mg/ml) and Evans blue (0.5 mg/ml). 30 Minutes after the antigen challenge, the rat was decapitated and exsanguinated. Then, the skin was reflected, and the area of blue spots was measured in milimeters by multiplying the longer diameter by the shorter diameter. The comparison was made with the diluted serum which showed 100 to 150 mm² in the average area of control. The degree of inhibition of the test compound is expressed by the following notations.

±: 0-25% inhibition with no significant difference from the control

±: 25-50% inhibition with a significant difference from the control

++: 50-75% inhibition with a significant difference from the control

+++: 75-100% inhibition with a significant difference from the control

Each test pharmaceutical compound was suspended in a 0.2% carboxymethylcellulose solution and administered orally at a rate of 100 mg/kg one hour prior to the antigen challenge. Disodium cromoglycate which was known as an anti-allergic drug was employed as a control or reference substance.

The results of tests (1) and (2) are shown in Table 1 in which each figure in the "Inhibition of Histamine Release" column denotes the lowest effective concentration to inhibit the release of histamine.

                  TABLE 1                                                          ______________________________________                                          ##STR18##           Inhibition of Histamine release (μg/ml)                                               P C A (p.o)                                     ______________________________________                                          ##STR19##            3                                                        3-CH.sub.3 7-CONHTz   3       ±                                             3-CH.sub.3 7-Tz       1       +                                                2-COOH                10      +                                                2-COOH 7-CH.sub.3     0.3     +                                                2-COOH 4-CH.sub.3     --      ++                                               2-COOH 7-tert.Bu      0.3     +++                                               ##STR20##            1       + +                                               ##STR21##            0.3     ±                                             2-CONHTz              0.1     +                                                2-CONHTz 7-tert.Bu    1       ±                                             2-Tz                  0.01    +                                                2-Tz 7-CH.sub.3       0.01    ±                                             2-Tz 4-CH.sub.3       0.1     +                                                2-Tz 7-tert.Bu        0.1     +                                                2-Tz 7-OCH.sub.3      --      +                                                 ##STR22##            10      +                                                2-Tz 7-COOH           0.01    +                                                3-COOH                10      +                                                3-Tz                  0.3     ++                                               3-Tz 7-CH.sub.3       --      ++                                               Disodium cromoglycate 3       ±                                             ______________________________________                                          Remarks:                                                                       ##STR23##                                                                

2. Acute toxic test

Each of the compounds shown in Table 2 was suspended in a 0.5% carboxymethylcellulose solution and administered orally to a male SD rat (5 weeks old). Upon the lapse of 72 hours after the administration, the LD₅₀ value was determined by the up-down method. The results are shown in Table 2.

                  TABLE 2                                                          ______________________________________                                          ##STR24##                LD.sub.50 (p.o)                                      ______________________________________                                         2-COOH                   >4000                                                 2-Tz                     >4000                                                  ##STR25##               >4000                                                  ##STR26##               >4000                                                 ______________________________________                                    

The compounds according to the invention can be applied by intravenous injection or oral administration, and their dose is preferably within a range of 10 to 1,000 mg/day.

The compounds according to the present invention are useful per se as pharmaceutical products as described above, but they may be dehydroenated to obtain their corresponding xanthone derivatives which possess anti-allergic and asthematreating activities.

This invention will be described in greater detail with reference to certain specific Examples.

EXAMPLE 1 7-Bromo-1,2,3,4-tetrahydro-9-xanthone

To 500 ml of a suspension solution of anhydrous chloroform containing 130 g of 5-bromoacetylsalicylic acid was added dropwise, at a temperature of below 0° C., 50.6 g of triethylamine to obtain a homogeneous solution. To the solution were further added dropwise, at a temperature of below -5° C., 54.3 g of ethylchloroformate and then 80.6 g of 1-pyrrolidinocyclohexene. The resulting solution was stirred for 4 hours during which the temperature of the solution was gradually lowered to room temperature. After removal of the solvent from the reaction mixture by distillation under reduced pressure, 400 ml of pyridine and 100 ml of water were combined with the residue thus obtained. Thereafter, the mixture was heated for 1 hour under refluxing and stirring conditions, and its solvent fractions were removed by distillation under reduced pressure. The resulting residue was allowed to stand overnight, followed by addition of 800 ml of water. The separated deposit was collected by filtration and air-dried. The deoposit was crystallized from ethanol to obtain 85.5 g (yield: 61.2%) of 7-bromo-1,2,3,4-tetrahydro-9-xanthone as white needle-like crystals having a melting point of 149° C.-150.5° C.

IR(ν_(max) ^(KBr) cm⁻¹): 1630 (C═O).

NMR (CDCl₃)δ: 8.33 (1H, d, J=3 Hz, Ar-H); 7.85-7.20 (2H, m, Ar-H); 2.92-2.48 [4H, m, (CH₂ at the C₁ and C₂ positions)]; 2.25-1.65 [4H, m, (CH₂ at the C₃ and C₄ positions)].

Elementary Analysis: As C₁₃ H₁₁ BrO₂

    ______________________________________                                                   C          H      Br                                                 Calculated (%)                                                                             55.93        3.97   28.63                                          Found (%)   56.03        4.11   28.61                                          ______________________________________                                    

EXAMPLES 2-11

Using the same operation as in Example 1, the tetrahydroxanthone derivatives shown in Table 1 were obtained.

                                      TABLE 1                                      __________________________________________________________________________                         Melting                                                                              Appearance             Elementary analysis                                                            values                                            Point (Recrystalization                                                                        Yield                                                                              Molecular                                                                               Calculated                                                                             Found (%)             Example                                                                             Compound       (°C.)                                                                         Solvent)  (%) formula  C   H   C  H                  __________________________________________________________________________     2    7-bromo-2-methyl-1,2,3,4-                                                                     190-191                                                                              White needle-like                                                                        52.7                                                                               C.sub.14 H.sub.13 BrO.sub.2                                                             57.36                                                                              4.47                                                                               57.45                                                                             4.44                    tetrahydro-9-xanthone                                                                               crystals                                                                       (ethanol)                                            3    7-bromo-2-(t-butyl)-1,2,3,4-                                                                  178-180                                                                              White prism-like                                                                         58.5                                                                               C.sub.17 H.sub.19 BrO.sub.2                                                             60.90                                                                              5.72                                                                               60.62                                                                             5.71                    tetrahydro-9-xanthone                                                                               crystals (chloro-                                                              form/ethanol)                                        4    2-benzoyloxy-7-bromo-                                                                         175-176                                                                              Colorless needle-                                                                        71.4                                                                               C.sub.20 H.sub.15 BrO.sub.4                                                             60.17                                                                              3.79                                                                               60.29                                                                             3.75                    1,2,3,4-tetrahydro-9-xanthone                                                                       like crystals                                        5    7-bromo-5-methyl-1,2,3,4-                                                                     170-172                                                                              White needle-like                                                                        47.0                                                                               C.sub.14 H.sub.13 BrO.sub.2                                                             57.36                                                                              4.47                                                                               57.36                                                                             4.40                    tetrahydro-9-xanthone                                                                               crystals                                                                       (ethanol)                                            6    7-bromo-6-methyl-1,2,3,4-                                                                     139.5-140.5                                                                          White prism-like                                                                         46.4                                                                               C.sub.14 H.sub.13 BrO.sub.2                                                             57.36                                                                              4.47                                                                               57.48                                                                             4.39                    tetrahydro-9-xanthone                                                                               crystals                                                                       (ethanol)                                            7    7-bromo-2,6-dimethyl-1,2,3,4-                                                                 149-150                                                                              White needle-like                                                                        43.0                                                                               C.sub.15 H.sub.15 BrO.sub.2                                                             58.64                                                                              4.92                                                                               58.55                                                                             4.82                    tetrahydro-9-xanthone                                                                               crystals (chloro-                                                              form/ethanol)                                        8    7-bromo-6-chloro-1,2,3,4-                                                                     160-161                                                                              White needle-like                                                                        43.6                                                                               C.sub.13 H.sub.10 BrClO.sub.2                                                           49.79                                                                              3.21                                                                               49.75                                                                             3.05                    tetrahydro-9-xanthone                                                                               crystals (chloro-                                                              form/ethanol)                                        9    5-bromo-7-chloro-1,2,3,4-                                                                     170-171                                                                              White needle-like                                                                        85.8                                                                               C.sub.13 H.sub.10 BrClO.sub.2                                                           49.79                                                                              3.21                                                                               49.83                                                                             3.09                    tetrahydro-9-xanthone                                                                               crystals (chloro-                                                              form/ethanol)                                        10   6-bromo-2-methyl-1,2,3,4-                                                                     160-163                                                                              White needle-like                                                                        65.5                                                                               C.sub.14 H.sub.13 BrO.sub.2                                                             57.36                                                                              4.47                                                                               57.42                                                                             4.22                    tetrahydro-9-xanthone                                                                               crystals                                                                       (ethanol)                                            11   6-bromo-2-(t-butyl)-1,2,3,4-                                                                  165-167                                                                              White powder                                                                             100 C.sub.17 H.sub.19 BrO.sub.2                                                             60.90                                                                              5.72                                                                               61.20                                                                             5.69                    tetrahydro-9-xanthone                                                     __________________________________________________________________________

EXAMPLE 12 5,6,7,8-Tetrahydro-9-oxo-xanthen-2-carbonitrile

A mixture of 252.6 g of 7-bromo-1,2,3,4-tetrahydro-9-xanthone obtained in Example 1, 89.1 g of cuprous cyanide and 900 ml of N-methyl-2-pyrrolidone was heated with stirring for 2 hours at 190° C. and then allowed to cool to 80° C. To the reaction mixture was added a mixture of 300 g of ferric chloride, 450 ml of water and 80 ml of concentrated hydrochloric acid, and the resulting solution was agitated for 30 minutes. After allowing the reaction mixture to stand overnight, the deposited crystals were collected by filtration and washed thoroughly with water. Subsequently, the crystals were dried and recrystallized from acetonitrile to obtain 169.6 g (yield: 83.6%) of 5,6,7,8-tetrahydro-9-oxo-xanthene-2-carbonitrile as brownish prism-like crystals having a melting point of 198° to 200° C.

IR(ν_(max) ^(KBr) cm⁻¹): 2280 (CN), 1650 (C═O).

NMR (CDCl₃)δ: 8.46 (1H, d, J=2 Hz, Ar-H); 7.96-7.27 (2H, m, Ar-H); 3.13-2.29 [4H, m, (CH₂ at the C₅ and C₆ positions)]; 2.29-1.55 [4H, m, (CH₂ at the C₇ and C₈ positions)].

Elementary Analysis: As C₁₄ H₁₁ NO₂

    ______________________________________                                                   C          H      N                                                  ______________________________________                                         Calculated (%)                                                                             74.65        4.92   6.22                                           Found (%)   74.56        4.88   6.10                                           ______________________________________                                    

EXAMPLES 13-26

Using the same operation as in Example 12, the cyanoderivatives of tetrahydroxanthone shown in Table 2 were obtained.

                                      TABLE 2                                      __________________________________________________________________________     Ex-               Melting                                                                              Appearance           Elementary analysis values        am-               Point (Recrystallization                                                                       Yield                                                                              Molecular                                                                             Calculated                                                                              Found (%)                ple                                                                               Compound       (°C.)                                                                         solvent)  (%) formula                                                                               C  H  N  C  H  N                  __________________________________________________________________________     13 7-methyl-5,6,7,8-tetrahydro-                                                                        Yellowish, leaf-                                                                         87.3                                                                               C.sub.15 H.sub.13 NO.sub.2                                                            75.30                                                                             5.48                                                                              5.85                                                                              74.85                                                                             5.49                                                                              5.75                  9-oxo-xanthene-2-carbonitrile                                                                 209-210                                                                              like crystals                                                                  (acetonitrile)                                         14 7-(t-butyl-5,6,7,8-tetrahydro-                                                                      White prism-like                                                                         78.0                                                                               C.sub.18 H.sub.19 NO.sub.2                                                            76.84                                                                             6.81                                                                              4.98                                                                              76.90                                                                             6.67                                                                              4.70                  9-oxo-xanthene-2-carbonitrile                                                                 204-206                                                                              crystals (dimethyl                                                             formamide)                                             15*                                                                               7-hydroxy-5,6,7,8-tetrahydro-                                                                       Light yellowish,                                                                         70.5                                                                               C.sub.14 H.sub.11 NO.sub.8                                                            69.70                                                                             4.59                                                                              5.80                                                                              69.99                                                                             4.43                                                                              5.71                  9-oxo-xanthene-2-carbonitrile                                                                 178-180                                                                              prism-like crys-                                                               tals (ethanol)                                         16 4-methyl-5,6,7,8-tetrahydro-                                                                        Yellowish needle-                                                                        58.4                                                                               C.sub.15 H.sub.13 NO.sub.2                                                            75.30                                                                             5.48                                                                              5.85                                                                              75.15                                                                             5.39                                                                              5.42                  9-oxo-xanthene-2-carbonitrile                                                                 212-214                                                                              like crystals (di-                                                             methyl formamide)                                      17 3-methyl-5,6,7,8-tetrahydro                                                                         White needle-like                                                                        88.4                                                                               C.sub.15 H.sub.13 NO.sub.2                                                            75.30                                                                             5.48                                                                              5.85                                                                              74.86                                                                             5.41                                                                              5.61                  9-oxo-xanthene-2-carbonitrile                                                                 198.5-200                                                                            crystals                                                                       (acetonitrile)                                         18 3,7-dimethyl-5,6,7,8-                                                                               White needle-like                                                                        75.8                                                                               C.sub.16 H.sub.15 NO.sub.2                                                            75.87                                                                             5.97                                                                              5.53                                                                              75.64                                                                             5.91                                                                              5.29                  tetrahydro-9-oxo-xanthene-                                                                    178.5-180                                                                            crystals                                                  2-carbonitrile       (acetonitrile)                                         19 3-chloro-5,6,7,8-tetrahydro-                                                                        White needle-like                                                                        56.9                                                                               C.sub.14 H.sub.10 ClNO.sub.2                                                          64.75                                                                             3.88                                                                              5.39                                                                              64.85                                                                             3.65                                                                              5.21                  9-oxo-xanthene-2-carbonitrile                                                                 222-224                                                                              crystals                                                                       (acetonitrile)                                         20 5,6,7,8-tetrahydro-9-                                                                               White leaf-like                                                                          100 C.sub.14 H.sub.11 NO.sub.2                                                            74.65                                                                             4.92                                                                              6.22                                                                              74.15                                                                             4.90                                                                              6.06                  oxo-xanthene-3-carbonitrile                                                                   168-172                                                                              crystals                                                                       (acetonitrile)                                         21 2-chloro-5,6,7,8-tetrahydro-                                                                        Yellowish powder                                                                         40.4                                                                               C.sub.14 H.sub.10 ClNO.sub.2                                                          64.75                                                                             3.88                                                                              5.39                                                                              64.53                                                                             3.65                                                                              5.41                  9-oxo-xanthene-4-carbonitrile                                                                 189-192                                                                              (acetonitrile)                                         22**                                                                              7-acetoxy-5,6,7,8-tetrahydro-                                                                       Colorless prism-                                                                         76.3                                                                               C.sub.18 H.sub.13 NO.sub.4                                                            67.84                                                                             4.63                                                                              4.95                                                                              68.12                                                                             4.51                                                                              4.88                  9-oxo-xanthene-2-carbonitrile                                                                 178   like crystals                                                                  (ethanol)                                              23***                                                                             7-methoxy-5,6,7,8-tetrahydro-                                                                       Colorless plate-                                                                         61.2                                                                               C.sub.15 H.sub.13 NO.sub.3                                                            70.58                                                                             5.13                                                                              5.49                                                                              70.32                                                                             5.28                                                                              5.51                  9-oxo-xanthene-2-carbonitrile                                                                 137-139                                                                              like crystals                                                                  (ethanol)                                              24 7-benzoyloxy-5,6,7,8-                                                                               Light brownish,                                                                          86.9                                                                               C.sub.21 H.sub.15 NO.sub.4                                                            73.03                                                                             4.38                                                                              4.06                                                                              73.31                                                                             4.27                                                                              4.15                  tetrahydro-9-oxo-xanthene-                                                                    220-222                                                                              prism-like                                                2-carbonitrile       crystals (di-                                                                  methyl formamide)                                      25 7-methyl-5,6,7,8-tetrahydro-                                                                        White powder                                                                             60.0                                                                               C.sub.15 H.sub.13 NO.sub.2                                                            75.30                                                                             5.48                                                                              5.85                                                                              74.92                                                                             5.31                                                                              5.68                  9-oxo-xanthene-3-carbonitrile                                                                 198-200                                                      26 7-(t-butyl)-5,6,7,8-tetrahydro-                                                                     White powder                                                                             53.0                                                                               C.sub.18 H.sub.19 NO.sub.2                                                            76.84                                                                             6.81                                                                              4.98                                                                              76.62                                                                             6.77                                                                              4.81                  9-oxo-xanthene-3-carbonitrile                                                                 182-187                                                      __________________________________________________________________________      *employed as the starting material the compound obtained in belowdescribe      Example 67.                                                                    **employed as the starting material the compound obtained in                   belowdescribed Example 69; and                                                 ***employed as the starting material the compound obtained in below            described Example 68.                                                    

EXAMPLE 27 5,6,7,8-Tetrahydro-9-oxo-xanthene-2-carboxylic acid

To 88.0 g of 5,6,7,8-tetrahydro-9-oxo-xanthene-2-carbonitrile obtained in Example 12 was added 1.5 l of a mixed solution of water-sulfuric acid-acetic acid (1:1:1), and the mixture was heated for 2 hours under refluxing and stirring conditions. After being cooled, the reaction mixture was combined with 1.5 l of water and then ice-cooled for 2 hours. The resulting crystal deposit was collected by filtration, washed with water and then air-dried. The deposit was recrystallized from acetic acid to obtain 84.9 g (yield: 88.5%) of 5,6,7,8-tetrahydro-9-oxo-xanthene-2-carboxylic acid as light yellowish prism-like crystals having a melting point of 253° to 255° C.

IR(_(max) ^(KBr) cm⁻¹): 1720 (COOH), 1620 (C═O).

NMR (DMSO-d₆)δ: 8.40 (1H, d, J=2 Hz, Ar-H); 8.25-7.95 (1H, m, Ar-H); 7.42 (1H, d, J=10 Hz, Ar-H); 2.82-2.10 [4H, m, (CH₂ at the C₅ and C₆ positions)]; 2.10-1.50 [4H, m, (CH₂ at the C₇ and C₈ positions)].

Elementary Analysis: As C₁₄ H₁₂ O₄

    ______________________________________                                                          C    H                                                        ______________________________________                                         Calculated (%)     68.84  4.95                                                 Found (%)          68.46  4.68                                                 ______________________________________                                    

EXAMPLES 28-40

Using the same operation as in Example 27, the carboxylic acid derivatives of tetrahydroxanthone shown in Table 3 were obtained.

                                      TABLE 3                                      __________________________________________________________________________                         Melting                                                                              Appearance           Elementary analysis                                                            values                                              Point (Recrystallization                                                                       Yield                                                                              Molecular                                                                             Calculated                                                                             Found (%)               Example                                                                             Compound       (°C.)                                                                         Solvent)  (%) formula                                                                               C   H   C   H                   __________________________________________________________________________                               Light yellowish                                      28   7-methyl-5,6,7,8-tetrahydro-9-                                                                235-237                                                                              needle-like crys-                                                                        88.7                                                                               C.sub.15 H.sub.14 O.sub.4                                                             69.75                                                                              5.46                                                                               69.68                                                                              5.40                     oxo-xanthene-2-carboxylic acid                                                                      tals(acetic acid)                                         7-(t-butyl)-5,6,7,8- White prism-like                                     29   tetrahydro-9-oxo-xanthene-                                                                    252-254                                                                              crystals  77.0                                                                               C.sub.18 H.sub.20 O.sub.4                                                             71.98                                                                              6.71                                                                               71.63                                                                              6.62                     2-carboxylic acid    (acetic acid)                                             4-methyl-5,6,7,8-tetrahydro-                                                                        White needle-like                                    30   9-oxo-xanthene-2-                                                                             287-290                                                                              crystals  75.0                                                                               C.sub.15 H.sub.14 O.sub.4                                                             69.75                                                                              5.46                                                                               69.43                                                                              5.43                     carboxylic acid      (acetic acid)                                             3-methyl-5,6,7,8-tetrahydro-                                                                        White needle-like                                    31   9-oxo-xanthene-2-                                                                             288-291                                                                              crystals  81.0                                                                               C.sub.15 H.sub.14 O.sub.4                                                             69.75                                                                              5.46                                                                               69.82                                                                              5.42                     carboxylic acid      (acetic acid)                                             3,7-dimethyl-5,6,7,8-                                                                               White prism-like                                     32   tetrahydro-9-oxo-xanthene-                                                                    268-271                                                                              crystals  76.0                                                                               C.sub.16 H.sub.16 O.sub.4                                                             70.57                                                                              5.92                                                                               70.65                                                                              5.92                     2-carboxylic acid    (acetic acid)                                             3-chloro-5,6,7,8-tetrahydro-9-                                                                      White prism-like                                     33   oxo-xanthene-2-carboxylic acid                                                                271-274                                                                              crystals  73.5                                                                               C.sub.14 H.sub.11 ClO.sub.4                                                           60.33                                                                              3.98                                                                               60.60                                                                              3.89                                          (acetic acid)                                             5,6,7,8-tetrahydro-9-oxo-                                                                           White needle-like                                    34   xanthene-3-carboxylic acid                                                                    278-281                                                                              crystals (chloro-                                                                        94.9                                                                               C.sub.14 H.sub.12 O.sub.4                                                             68.85                                                                              4.95                                                                               68.61                                                                              4.86                                          form/methanol)                                            2-chloro-5,6,7,8-tetrahydro-9-                                                                      Yellowish prism-                                     35   oxo-xanthene-4-carboxylic acid                                                                264-266.5                                                                            like crystals (chlo-                                                                     57.0                                                                               C.sub.14 H.sub.11 ClO.sub.4                                                           60.33                                                                              3.98                                                                               60.08                                                                              3.82                                          roform/methanol)                                          2-chloro-7-methyl-5,6,7,8-                                                                          White prism-like                                     36   tetrahydro-9-oxo-xanthene-                                                                    254-255                                                                              cristals (chloro-                                                                        79.3                                                                               C.sub.15 H.sub.13 ClO.sub.4                                                           60.53                                                                              4.42                                                                               60.54                                                                              4.47                     4-carboxylic acid    form/methanol)                                            6-(i-butyl)-5,6,7,8-                                                      37   tetrahydro-9-oxo-xanthene-                                                                    240-242                                                                              *1        56.1                                                                               C.sub.18 H.sub.20 O.sub.4                                                             71.74                                                                              6.68                                                                               71.98                                                                              6.71                     2-carboxylic acid                                                              6-(i-butyl)-4-methyl-5,6,7,8-                                                                       Colorless needle-                                    38   tetrahydro-9-oxo-xanthene-                                                                    253-255                                                                              like crystals                                                                            77.4                                                                               C.sub.19 H.sub.22 O.sub.4                                                             72.04                                                                              6.97                                                                               72.59                                                                              7.05                     2-carboxylic acid    (acetic acid)                                             7-methyl-5,6,7,8-tetrahydro-9-                                            39   oxo-xanthene-3-carboxylic acid                                                                284-290                                                                              *2        67.0                                                                               C.sub.15 H.sub.14 O.sub.4                                                             69.75                                                                              5.46                                                                               69.39                                                                              5.50                     7-(t-butyl)-5,6,7,8-tetra-                                                                    310   White prism-like                                     40   hydro-9-oxo-xanthene-                                                                         (de-  cristals  43.0                                                                               C.sub.18 H.sub.20 O.sub.4                                                             71.98                                                                              6.71                                                                               71.68                                                                              6.62                     3-carboxylic acid                                                                             composed)                                                                            (acetic acid)                                        __________________________________________________________________________      *1: Light yellowish needlelike crystals (chloroform/methanol)                  *2: Light yellowish needlelike crystals (acetic acid)                    

EXAMPLE 41 2-(N-Morpholinocarbonyl)-5,6,7,8-tetrahydro-9-xanthone

To a suspension solution containing 3.36 g of 5,6,7,8-tetrahydro-9-oxo-xanthene-2-carboxylic acid obtained in Example 27 and 50 ml of anhydrous chloroform was added 5 ml of thionyl chloride, and the mixture was heated for 3 hours under refluxing and stirring conditions. Thereafter, the solvent was distilled off under reduced pressure, and the residue was dissolved in 60 ml of anhydrous chloroform. The thus prepared solution was charged dropwise into 100 ml of anhydrous chloroform containing 4.36 g of morpholine and heated for 3 hours under refluxing and stirring conditions. After being cooled, the reaction mixture was combined with water, and the resulting solution was extracted with chloroform. The chloroform phase was washed with water and then dried with magnesium sulfate. After removal of the solvent by distillation, the residual oil was crystallized from dioxane to obtain 3.00 g (yield: 63.9%) of 2-(N-morpholinocarbonyl)-5,6,7,8-tetrahydro-9-xanthone as a light yellowish powder having a melting point of 186.5° to 188° C.

IR(_(max) ^(KBr) cm⁻¹): 1640 (CON), 1620 (C═O).

NMR (CDCl₃)δ: 8.18 (1H, d, j=2 Hz, Ar-H); 7.85-7.27 (2H, m, Ar-H); 3.68 (8H, s, ##STR27## 2.89-2.30 [4H, m, (CH₂ at the C₅ and C₆ positions)]; 2.30-1.57 [4H, m, (CH₂ at the C₇ and C₈ positions)].

Elementary Analysis: As C₁₈ H₁₉ NO₄

    ______________________________________                                                       C      H         N                                               ______________________________________                                         Calculated (%)  68.99    6.11      4.47                                        Found (%)       68.71    6.14      4.22                                        ______________________________________                                    

EXAMPLES 42-53

Using the same operation as in Example 41, the hydroxanthone derivatives shown in Table 4 were obtained.

                                      TABLE 4                                      __________________________________________________________________________     Ex-                Melting                                                                             Appearance           Elementary analysis values        am-                Point                                                                               (Recrystallization                                                                      Yield                                                                              Molecular                                                                              Calculated                                                                              Found (%)                ple                                                                               Compound        (°C.)                                                                        Solvent) (%) formula C  H  N  C  H  N                  __________________________________________________________________________     42 5,6,7,8-tetrahydro-N-(5'-                                                                      285  Yellowish powder                                          tetrazolyl)-9-oxo-xanthene-2-                                                                  (decom-                                                                             (water/dimethyl                                                                         66.4                                                                               C.sub.15 H.sub.13 N.sub.5 O.sub.3                                                      57.87                                                                             4.21                                                                              22.50                                                                             57.99                                                                             4.21                                                                              22.87                 carboxylic acid amide                                                                          posed)                                                                              formamide)                                             43 N-(2'-methoxycarbonylphenyl)-                                                                       Yellow prism-like                                         5,6,7,8-tetrahydro-9-oxo-                                                                      240-242                                                                             crystals 78.8                                                                               C.sub.22 H.sub.19 NO.sub.5                                                             70.02                                                                             5.07                                                                              3.71                                                                              70.30                                                                             4.96                                                                              3.48                  xanthene-2-carboxylic acid                                                                          (dioxane)                                                 amide                                                                       44 N-(2'-methoxycarbonylphenyl)-                                                                       Yellowish prism-                                          7-methyl-5,6,7,8-tetrahydro-9-                                                                 201-203                                                                             like crystals                                                                           58.3                                                                               C.sub.23 H.sub.21 NO.sub.5                                                             70.57                                                                             5.41                                                                              3.58                                                                              70.18                                                                             5.38                                                                              3.44                  oxo-xanthene-2-carboxylic                                                                           (dioxane)                                                 acid amide                                                                  45 7-methyl-5,6,7,8-tetrahydro-                                                                        Yellowish powder                                          N-(5'-tetrazolyl)-9-oxo-                                                                       269-270                                                                             (water/dimethyl                                                                         34.3                                                                               C.sub.16 H.sub.15 N.sub.5 O.sub.3                                                      59.07                                                                             4.65                                                                              21.53                                                                             58.67                                                                             4.40                                                                              21.20                 xanthene-2-carboxylic acid                                                                     (decom-                                                                             formamide)                                                amide           posed)                                                      46 7-(t-butyl)-N-(2'-methoxy-                                                                          Light yellowish                                           carbonylphenyl)-5,6,7,8-                                                                            needle-like                                                                             64.0                                                                               C.sub.26 H.sub.27 NO.sub.5                                                             72.04                                                                             6.28                                                                              3.23                                                                              71.67                                                                             6.19                                                                              2.91                  tetrahydro-9-oxo-xanthene-                                                                     197-198                                                                             crystals                                                  2-carboxylic acid amide                                                                             (dioxane)                                              47 7-(t-butyl)-5,6,7,8- Light yellowish                                           tetrahydro-N-(5'-tetrazolyl)-                                                                  300.5                                                                               powder   39.8                                                                               C.sub.19 H.sub.21 N.sub.5 O.sub.3                                                      62.11                                                                             5.76                                                                              19.06                                                                             61.98                                                                             5.57                                                                              19.37                 9-oxo-xanthene-2-carboxylic                                                                    (decom-                                                                             (dimethyl                                                 acid amide      posed)                                                                              formamide)                                             48 7-bromo-N-(2'-methoxycarbonyl-                                                                      Brownish prism-                                           phenyl)-1,2,3,4-tetrahydro-                                                                    181-183                                                                             like crystals                                                                           40.7                                                                               C.sub.22 H.sub.18 BrNO.sub.5                                                           57.90                                                                             3.98                                                                              3.07                                                                              57.66                                                                             4.01                                                                              3.02                  9-oxo-xanthene-2-carboxylic                                                                         (dioxane)                                                 acid amide                                                                  49 7-bromo-1,2,3,4-tetrahydro-N-                                                                  300 or                                                                              Yellowish powder                                                                        79.3                                                                               C.sub.15 H.sub.12 BrN.sub.5 O.sub.3                                                    46.16                                                                             3.10                                                                              17.95                                                                             45.89                                                                             2.93                                                                              18.24                 (5'-tetrazolyl)9-oxo-xanthene-                                                                 high (dimethyl                                                 2-carboxylic acid amide                                                                             formamide)                                             50 6-methyl-N-(2'-methoxycarbonyl-                                                                192-193.5                                                                           Light yellowish                                           phenyl)-1,2,3,4-tetrahydro-9-                                                                  (decom-                                                                             prism-like                                                                              79.3                                                                               C.sub.23 H.sub.21 NO.sub.5                                                             70.57                                                                             5.41                                                                              3.58                                                                              70.55                                                                             5.43                                                                              3.25                  oxo-xanthene-2-carboxylic                                                                      posed)                                                                              crystals                                                  acid amide           (dioxane)                                              51 6-methyl-2-(N-methylpipe-                                                                           Yellowish                                                 razinocarbonyl)-1,2,3,4-                                                                       136.5-138                                                                           powder   15.3                                                                               C.sub.20 H.sub.24 N.sub.2 O.sub.3                                                      70.56                                                                             7.11                                                                              8.23                                                                              70.14                                                                             6.99                                                                              8.00                  tetrahydro-9-xanthone                                                                               (dioxane)                                              52 6-methyl-2-(morpholino-                                                        carbonyl)-1,2,3,4-                                                                             183-185                                                                             White powder                                                                            59.9                                                                               C.sub.19 H.sub.21 NO.sub.4                                                             69.70                                                                             6.47                                                                              4.28                                                                              69.59                                                                             6.41                                                                              4.11                  tetrahydro-9-xanthone                                                                               (dioxane)                                              53 5-methyl-N-(2'methoxycarbonyl-                                                                      Yellowish                                                 phenyl)-1,2,3,4-tetrahydro-                                                                    214-216                                                                             powder   63.4                                                                               C.sub.23 H.sub.21 NO.sub.5                                                             70.57                                                                             5.41                                                                              3.58                                                                              70.80                                                                             5.35                                                                              3.48                  9-oxo-xanthene-2-carboxylic                                                                         (dioxane)                                                 acid amide                                                                  __________________________________________________________________________

EXAMPLE 54 1,2,3,4-Tetrahydro-7-(5'-tetrazolyl)-9-xanthone

To 150 g of 5,6,7,8-tetrahydro-9-oxo-xanthene-2-carbonitrile obtained in Example 12 were added 52.5 g of sodium azide, 42.9 g of ammonium chloride and 600 ml of dimethyl formamide. The mixture was agitated at 120° C. for 24 hours, and dimethyl formamide was then distilled off under reduced pressure. To the residue was first added 500 ml of water and then 300 ml of a 5% aqueous sodium hydroxide solution in a dropwise fashion to dissolve the residual deposit. The water phase was washed once with ether and acidified to adjust its pH to 2 with 10% hydrochloric acid to form a deposit, which deposit was then collected by filtration and recrystallized from dimethyl formamide to obtain 106 g (yield: 83.6%) of 1,2,3,4-tetrahydro-7-(5'-tetrazolyl)-9-xanthone as an orange-colored powder having a melting point of 299° to 300° C. (decomposed).

IR(ν_(max) ^(KBr) cm⁻¹): 1620 (C═O).

Elementary Analysis: As C₁₄ H₁₂ N₄ O₂

    ______________________________________                                                       C      H         N                                               ______________________________________                                         Calculated (%)  62.68    4.51      20.89                                       Found (%)       62.50    4.41      21.07                                       ______________________________________                                    

MS (m/e): 268 [M⁺ ].

EXAMPLES 55-65

Using the same operation as in Example 54, the tetrazolyl derivatives of tetrahydroxanthone shown in Table 5 were obtained.

                                      TABLE 5                                      __________________________________________________________________________                       Melting                                                                              Appearance           Elementary analysis values        Ex-               Point (Recrystallization                                                                      Yield                                                                              Molecular                                                                              Calculated                                                                              Found (%)                ample                                                                              Compound      (°C.)                                                                         Solvent) (%) formula C  H  N  C  H  N                  __________________________________________________________________________     55  2-methyl-1,2,3,4-tetrahydro-                                                                 271.5 Yellowish powder                                           7-(5'tetrazolyl)-9-xanthone                                                                  (de-  (water/dimethyl                                                                         35.0                                                                               C.sub.15 H.sub.12 N.sub.4 O.sub.4                                                      57.69                                                                             3.87                                                                              17.98                                                                             56.82                                                                             3.76                                                                              17.81                                composed)                                                                            formamide)                                             56  2-(t-butyl)-1,2,3,4-tetrahydro-                                                                    Light-yellowish                                            7-(5'-tetrazolyl)-9-xanthone                                                                 275.5-276.5                                                                          needle-like                                                                             37.5                                                                               C.sub.18 H.sub.20 N.sub.4 O.sub.4                                                      66.65                                                                             6.22                                                                              17.27                                                                             66.31                                                                             6.23                                                                              17.41                                      crystals (dimethyl                                                             formamide)                                             57  4-methyl-5,6,7,8-tetrahydro-                                                                       Yellowish brown                                                                         46.2                                                                               C.sub.15 H.sub.14 N.sub.4 O.sub.2                                                      63.82                                                                             5.00                                                                              19.85                                                                             63.47                                                                             5.10                                                                              20.25                  2-(5'-tetrazolyl)-9-xanthone                                                                       powder (dimethyl                                                               formamide)                                             58  5,6,7,8-tetrahydro-3-                                                                        285   Light yellowish                                                                         71.9                                                                               C.sub.14 H.sub.12 N.sub.4 O.sub.2                                                      62.68                                                                             4.51                                                                              20.88                                                                             62.97                                                                             4.51                                                                              21.34                  (5'-tetrazolyl)-9-xanthone                                                                   (de-  powder (dimethyl                                                         composed)                                                                            formamide)                                             59  2-hydroxy-1,2,3,4-tetrahydro-                                                                303            73.2                                                                               C.sub.14 H.sub.12 N.sub.4 O.sub.3                                                      59.15                                                                             4.26                                                                              19.71                                                                             59.13                                                                             4.36                                                                              19.85                  7-(5'-tetrazolyl)-9-xanthone                                                                 (de-  */1                                                                      composed)                                                    60  2-acetoxy-1,2,3,4-tetrahydro-                                                                260-261                                                                              Colorless needle-                                          7-(5'-tetrazolyl)-9-xanthone                                                                 (de-  like crystals (di-                                                                      51.4                                                                               C.sub.16 H.sub.14 N.sub.4 O.sub.4                                                      58.89                                                                             4.32                                                                              17.17                                                                             58.76                                                                             4.43                                                                              17.48                                composed)                                                                            methyl formamide)                                      61  2-methoxy-1,2,3,4-tetrahydro-                                                                261-263                                                                              Colorless needle-                                          7-(5'-tetrazolyl)-9-xanthone                                                                 (de-  like crystals (di-                                                                      74.9                                                                               C.sub.15 H.sub.14 N.sub.4 O.sub.3                                                      60.40                                                                             4.73                                                                              18.78                                                                             60.33                                                                             4.78                                                                              19.14                                composed)                                                                            methyl formamide)                                      62  2-benzoyloxy-1,2,3,4-                                                                        283-284                                                          tetrahydro-7-(5'-tetrazolyl)-                                                                (de-  */2      62.2                                                                               C.sub.21 H.sub.10 N.sub.4 O.sub.4                                                      64.94                                                                             4.15                                                                              14.43                                                                             64.62                                                                             4.25                                                                              14.83                  9-xanthone    composed)                                                    63  7-chloro-2-methyl-1,2,3,4-                                                                   251-255                                                                              White powder                                               tetrahydro-5-(5'-tetrazolyl)-                                                                (de-  (chloroform/                                                                            50.0                                                                               C.sub.15 H.sub.13 ClN.sub.4 O.sub.2                                                    55.61                                                                             3.90                                                                              18.20                                                                             55.88                                                                             4.18                                                                              17.69                  9-xanthone    composed)                                                                            methanol)                                              64  2-methyl-1,2,3,4-tetrahydro-                                                                 265   Yellowish powder                                           6-(5'-tetrazolyl)-9-xanthone                                                                 (de-  (chloroform/                                                                            53.0                                                                               C.sub.15 H.sub.14 N.sub.4 O.sub.2                                                      63.82                                                                             5.00                                                                              19.85                                                                             64.02                                                                             4.98                                                                              20.09                                composed)                                                                            methanol)                                              65  2-(t-butyl)-1,2,3,4-                                                                         300   Light yellowish                                            tetrahydro-6-(5'-tetrazolyl)-                                                                (de-  powder (dimethyl                                                                        61.0                                                                               C.sub.18 H.sub.20 N.sub.                                                               66.65ub.2                                                                         6.22                                                                              17.27                                                                             66.33                                                                             6.12                                                                              17.11                  9-xanthone    composed)                                                                            formamide)                                             __________________________________________________________________________      */1: Light yellowish needlelike crystals (dimethyl formamide)                  */2: Colorless needlelike crystals (dimethyl formamide/ethanol)          

EXAMPLE 66-a 6-Methyl-1,2,3,4-tetrahydro-9-oxo-xanthene-9-oxo-xanthene-2-carbonitrile

To 15 ml of a dimethyl formamide suspension solution containing 1.0 g of 6-methyl-1,2,3,4-tetrahydro-9-oxo-xanthene-2-carboxylic acid amide was amide was added dropwise 1.19 g of thionyl chloride at 0° C., and the mixture was stirred for 30 minutes. The resulting mixture was then poured into iced water and decomposed. The separated powder was recrystallized from acetone to obtain 0.40 g (yield: 41%) of 6-methyl-1,2,3,4-tetrahydro-9-oxo-xanthene-2-carbonitrile as a white powder having a melting point of 176° to 178° C.

IR(ν_(max) ^(KBr) cm⁻¹): 2240 (CN), 1630 (C═O).

NMR (CDCl₃)δ: 8.11-7.90 (1H, m, Ar-H); 7.29-7.07 (2H, m, Ar-H); 3.08-2.60 [5H, m, (CH₂ at the C₁ and C₃ positions, CH at the C₂ positions)]; 2.46 (3H, s, CH₃); 2.60-1.92 [2H, m, (CH₂ at the C₄ positions)].

Elementary Analysis: As C₁₅ H₁₃ NO₂

    ______________________________________                                                      C       H         N                                               ______________________________________                                         Calculated (%) 75.30     5.48      5.85                                        Found (%)      74.92     5.47      5.75                                        ______________________________________                                    

EXAMPLE 66-b 6-Methyl-1,2,3,4-tetrahydro-2-(5'-tetrazolyl)-9-oxo-xanthene

To 4.30 g of 6-methyl-1,2,3,4-tetrahydro-9-oxo-xanthene-2-carbonitrile were added 1.40 g of sodium azide, 1.15 g of ammonium chloride and 25 ml of dimethyl formamide. The mixture was stirred at 120° C. for 24 hours. After completion of the reaction, water was added to the reaction mixture to dissolve any undissolved matter contained therein with a diluted aqueous sodium hydroxide solution. The resulting solution was filtered, and the filtrate was acidified with concentrated hydrochloric acid to form a crystalline deposit which was then crystallized from dimethyl formamide to obtain 3.50 g (yield: 76.0%) of 6-methyl-1,2,3,4-tetrahydro-2-(5'-tetrazolyl)-9-oxo-xanthene as a yellow powder having a melting point of 260° to 263° C. (decomposed).

IR(_(max) ^(KBr) cm⁻¹): 1620 (C═O).

NMR (CF₃ COOH)δ: 8.48-8.24 (1H, m, Ar-H); 7.79-7.54 (2H, m, Ar-HO); 4.17-3.15 [5H, m, (CH₂ at the C₁ and C₃ positions, CH at the C₂ positions)]; 3.15-2.22 [2H, m, (CH₂ at the C₄ position)]; 2.71 (3H, s, CH₃).

Elementary Analysis: As C₁₅ H₁₄ N₄ O₂

    ______________________________________                                                      C       H         N                                               ______________________________________                                         Calculated (%) 63.82     5.00      19.85                                       Found (%)      63.47     4.95      20.09                                       ______________________________________                                    

EXAMPLE 67 7-Bromo-2-hydroxy-1,2,3,4-tetrahydro-9-oxo-xanthene

45.0 g of 2-benzoyloxy-7-bromo-1,2,3,4-tetrahydro-9-oxo-xanthene obtained in Example 4 was suspended in a mixed solution of 240 ml of tetrahydrofuran and 90 ml of methanol. To the suspension was added dropwise at room temperature 45 ml of an aqueous solution containing 7.0 g of potassium hydroxide. After stirring the resulting solution for two hours, the solvent was removed by distillation. To the thus obtained crystals was added 300 ml of water, and the mixture was thoroughly agitated and filtered. The filtrate was recrystallized from ethanol to obtain 26.6 g (yield: 79.8%) of 7-bromo-2-hydroxy-1,2,3,4-tetrahydro-9-oxo-xanthene as light yellowish prism-like crystals.

IR(ν_(max) ^(KBr) cm⁻¹): 3390 (OH), 1600 (C═O).

NMR (CDCl₃)δ: 8.28 (1H, d, J=2 Hz, C₈ -H); 7.72 (1H, d, d, J=2 Hz, 8 Hz, C₆ -H); 7.27 (1H, d, J=8 Hz, C₅ -H); 4.50-4.12 (1H, m, C₂ -H); 2.90 (1H, d, J=3 Hz, OH); 3.10-2.60 [4H, m, (CH₂ at the C₁ and C₄ positions)]; 2.27-1.80 [2H, m, (CH₂ at the C₃ position)].

Elementary Analysis: As C₁₃ H₁₁ BrO₃

    ______________________________________                                                        C         H                                                     ______________________________________                                         Calculated (%)   52.91       3.76                                              Found (%)        53.09       3.69                                              ______________________________________                                    

EXAMPLE 68 7-Bromo-2-methoxy-1,2,3,4-tetrahydro-9-xanthone

To 100 ml of an anhydrous tetrahydrofuran solution containing 5.9 g of 7-bromo-2-hydroxy-1,2,3,4-tetrahydro-9-xanthone obtained in Example 67 was added 1.1 g of sodium hydroxide (as 55% dispersed in an oil). The mixture was stirred at 50° C. for 1 hour to which was then added dropwise 3.3 g of dimethylsulfate. The resulting mixture was agitated at 60° C. for 1.5 hours. After completion of the reaction, the solvent was removed by distillation to give a residue to which were added chloroform and water. The chloroform phase was collected and washed with water, and then dried with anhydrous sodium sulfate and purified by chromatography on silica gel. The crude crystals thus obtained were recrystallized from benzene/hexane to obtain 3.87 g (yield: 62.6%) of 7-bromo-2-methoxy-1,2,3,4-tetrahydro-9-xanthone as colorless needlelike crystals having a melting point of 139° to 142° C.

IR(ν_(max) ^(KBr) cm⁻¹): 1625 (C═O).

NMR (CDCl₃)δ: 8.24 (1H, d, J=2 Hz, Ar-H); 7.66 (1H, d, d, J=2 Hz, 8 Hz, Ar-H); 7.20 (1H, d, J=9 Hz, Ar-H); 3.70 (1H, q, J=5 Hz, C₂ -H); 3.38 (3H, s, OCH₃); 2.88-2.50 (4H, m, CH₂ at the C₁ and C₄ positions); 2.20-1.80 (2H, m, CH₂ at the C₃ position).

EXAMPLE 69 2-Acetoxy-7-bromo-1,2,3,4,-tetrahydro-9-xanthone

To 8.9 g of 7-bromo-2-hydroxy-1,2,3,4-tetrahydro-9-xanthone obtained in Example 67 were added 6.2 g of anhydrous acetic acid and 40 ml of pyridine. The mixture was stirred for 4 hours at 60° C., and after completion of the reaction, the solvent was removed by distillation. The resulting crystals were recrystallized from ethanol to obtain 9.9 g (yield: 97.9%) of 2-acetoxy-7-bromo-1,2,3,4-tetrahydro-9-xanthone as colorless needle-like crystals having a melting point of 177.5° to 178° C.

IR(ν_(max) ^(KBr) cm⁻¹): 1720 (OCOCH₃), 1620 (C═O).

NMR (CDCl₃)δ: 8.30 (1H, d, J=2 Hz, Ar-H); 7.73 (1H, d, d, J=2 Hz, 9 Hz, Ar-H); 7.28 (1H, d, J=9 Hz, Ar-H); 5.27 (1H, q, J=5 Hz, C₂ -H); 3.00-2.60 (4H, m, CH₂ at the C₁ and C₄ positions); 2.30-1.87 (2H, m, CH₂ at the C₃ position); 2.05 (3H, s, OCOCH₃).

Elementary Analysis: As C₁₅ H₁₃ O₄ Br

    ______________________________________                                                        C         H                                                     ______________________________________                                         Calculated (%)   53.43       3.89                                              Found (%)        53.58       3.84                                              ______________________________________                                    

EXAMPLE 70 N-(2'-Carboxyphenyl)-5,6,7,8-tetrahydro-9-oxo-xanthene-2-carboxylic acid amide

To 80 ml of a methanol suspension containing 4.31 of N-(2'-methoxycarbonylphenyl)-5,6,7,8tetrahydro-9-oxo-xanthene-2-carboxylic acid amide obtained in Example 43 was added 10 ml of an aqueous solution containing 0.48 g of sodium hydroxide. The mixture was heated for 3 hours under refluxing and stirring conditions. The solvent was then removed by distillation to give a residue which was dissolved in hot water and filtered. The filtrate was acidified with concentrated hydrochloric acid to separate a yellowish white deposit. The deposit was collected by filtration, washed with water and then air-dried. Finally, the deposit was recrystallized from acetic acid to obtain 2.96 g (yield: 71.8%) of N-(2'-carboxyphenyl)-5,6,7,8-tetrahydro-9-oxo-xanthene-2-carboxylic acid amide.

IR(ν_(max) ^(KBr) cm⁻¹): 3200-2700 (COOH), 1670 (COOH), 1620 (C═O).

NMR (CF₃ COOH)δ: 9.16-7.22 (7H, m, Ar-H); 3.38-2.67 [4H, m, (CH₂ at the C₅ and C₆ positions)]; 2.32-1.82 [4H, m, (CH₂ at the C₇ and C₈ positions)].

Elementary Analysis: As C₂₁ H₁₇ O₅ N

    ______________________________________                                                      C       H         N                                               ______________________________________                                         Calculated (%) 69.41     4.72      3.86                                        Found (%)      69.33     4.74      3.61                                        ______________________________________                                    

EXAMPLE 71-75

Using the same operation as in Example 70, the tetrahydroxanthone derivatives shown in Table 6 were obtained.

                                      TABLE 6                                      __________________________________________________________________________                         Melting                                                                             Appearance          Elementary analysis values        Ex-                 Point                                                                               (Recrystallization                                                                      Yield                                                                              Molecular                                                                             Calculated                                                                              Found (%)                ample                                                                              Compound        (°C.)                                                                        Solvent) (%) formula                                                                               C  H  N  C  H  N                  __________________________________________________________________________     71  N-(2'-carboxyphenyl)-7-methyl-                                                                      Yellowish powder                                          5,6,7,8-tetrahydro-9-oxo-                                                                      245-247                                                                             (acetic acid)                                                                           79.5                                                                               C.sub.22 H.sub.19 NO.sub.5                                                            70.02                                                                             5.07                                                                              3.71                                                                              69.74                                                                             5.06                                                                              3.71                   xanthene-2-carboxylic acid                                                     amide                                                                      72  7-(t-butyl)-N-(2-'carboxyphenyl)-                                                              262-264.5                                                                           White powder                                              5,6,7,8-tetrahydro-9-oxo-                                                                      (de- (acetic acid)                                                                           65.9                                                                               C.sub.26 H.sub.25 NO.sub.5                                                            71.58                                                                             6.01                                                                              3.34                                                                              71.05                                                                             5.97                                                                              3.18                   xanthene-2-carboxylic acid                                                                     composed)                                                      amide                                                                      73  7-bromo-N-(2'carboxyphenyl)-                                                                        White prism-like                                          1,2,3,4-tetrahydro-9-oxo-                                                                      235-236.5                                                                           crystals 66.0                                                                               C.sub.21 H.sub.16 BrNO.sub.5                                                          57.02                                                                             3.65                                                                              3.17                                                                              56.69                                                                             3.57                                                                              3.19                   xanthene-2-caboxylic acid                                                                           (acetic acid)                                             amide                                                                      74  6-methyl-N-(2'-carboxyphenyl)-                                                                 242-245.5                                                                           Colorless plate-                                          1,2,3,4-tetrahydro-9-oxo-                                                                      (de- like crystals                                                                           68.0                                                                               C.sub.22 H.sub.19 NO.sub.5                                                            70.02                                                                             5.07                                                                              3.71                                                                              69.91                                                                             5.16                                                                              3.84                   xanthene-2-carboxylic acid                                                                     composed)                                                                           (dimethyl                                                 amide                formamide)                                            75  5-methyl-N-(2'-carboxyphenyl)-                                                                      Light yellowish                                           1,2,3,4-tetrahydro-9-oxo-                                                                      250.5-252                                                                           prism-like                                                                              53.5                                                                               C.sub.22 H.sub.19 NO.sub.5                                                            70.02                                                                             5.07                                                                              3.71                                                                              69.84                                                                             4.90                                                                              3.66                   xanthene-2-carboxylic acid                                                                          crystals                                                  amide                (acetic acid)                                         __________________________________________________________________________ 

What is claimed is:
 1. A tetrahydroxanthone compound of the formula: ##STR28## wherein R₁ and R₂ are each halogen, cyano, lower alkyl or carboxyl and R is hydrogen or lower alkyl.
 2. A tetrahydroxanthone compound of the formula: ##STR29## wherein R₁ is halogen, cyano, lower alkyl or carboxyl, R₂ is halogen or lower alkyl and R is hydrogen or lower alkyl.
 3. A tetrahydroxanthone compound of the formula: ##STR30## wherein R₁ is halogen, cyano, or carboxyl and R is butyl, lower alkanoyloxy, benzoyloxy or ##STR31## wherein the phenyl ring may be substituted by carboxyl or alkyloxycarbonyl.
 4. A tetrahydroxanthone compound of the formula: ##STR32## wherein R₁ is halogen, cyano or carboxyl and R is loweralkanoyloxy, benzoyloxy or ##STR33## wherein the phenyl ring may be substituted by carboxyl or alkyloxycarbonyl.
 5. A tetrahydroxanthone compound of the formula: ##STR34## wherein R₁ or R is --CONR₃ R₄, wherein R₃ is hydrogen, R₄ is phenyl which may be substituted or R₃ and R₄ together with the amido nitrogen atom are morpholino or piperazino and the remaining R₁ or R group is hydrogen or lower alkyl.
 6. The compound of claim 1, wherein R₁ is carboxyl, R₂ is lower alkyl and R is hydrogen.
 7. The compound of claim 3, wherein R₁ is carboxyl, and R is butyl.
 8. The compound of claim 5, wherein R₁ is ##STR35## wherein said phenyl ring is substituted by a carboxyl group and R is lower alkyl or hydrogen.
 9. The compound of claim 3, wherein R₁ is 2-CO₂ H and R is 7-t-butyl. 